U.S. patent application number 10/505299 was filed with the patent office on 2005-10-13 for cosmetic formulations containing l-arginine oligomers.
Invention is credited to Cifra, Pamela N., Dake, Michael, Elkins, Christopher J., Waugh, Jacob.
Application Number | 20050226821 10/505299 |
Document ID | / |
Family ID | 27766011 |
Filed Date | 2005-10-13 |
United States Patent
Application |
20050226821 |
Kind Code |
A1 |
Waugh, Jacob ; et
al. |
October 13, 2005 |
Cosmetic formulations containing l-arginine oligomers
Abstract
Oligomers of L-arginine may be used to provide prophylactic or
therapeutic cosmetic or other enhancements to keratinous tissues
such as skin, hair, lips and gums through vasodilation. Topical
compositions preferably comprise (a) an enhancing effective amount
of an oligomer having from 7 to 15 subunits, each subunit
consisting of a member of the group selected from L-arginine and
physiologically acceptable salts of L-arginine that enhance
vasodilation through production of nitric oxide, and (b) a
cosmetically or dermatologically acceptable vehicle.
Inventors: |
Waugh, Jacob; (Palo Alto,
CA) ; Dake, Michael; (Stanford, CA) ; Elkins,
Christopher J.; (Palo Alto, CA) ; Cifra, Pamela
N.; (Hillsborough, CA) |
Correspondence
Address: |
Morgan & Finnegan
3 World Financial Center
New York
NY
10281-2101
US
|
Family ID: |
27766011 |
Appl. No.: |
10/505299 |
Filed: |
August 20, 2004 |
PCT Filed: |
February 21, 2003 |
PCT NO: |
PCT/US03/05399 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60358879 |
Feb 22, 2002 |
|
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|
Current U.S.
Class: |
424/50 ; 424/59;
424/70.14; 514/15.1; 514/18.8; 514/20.1; 514/20.7 |
Current CPC
Class: |
C07K 7/06 20130101; A61Q
19/00 20130101; A61K 38/08 20130101; A61K 8/88 20130101; A61Q 7/00
20130101; A61Q 1/10 20130101; A61K 38/10 20130101; A61Q 1/04
20130101; A61K 8/64 20130101 |
Class at
Publication: |
424/050 ;
514/014; 514/015; 514/016; 424/070.14; 424/059 |
International
Class: |
A61K 038/10; A61K
038/08; A61K 007/28; A61K 007/42; A61K 007/06; A61K 007/11 |
Claims
What is claimed is:
1. A composition for enhancement of keratinous tissues comprising
(a) an enhancing effective amount of a polymer having from 7 to 15
subunits, each subunit consisting of a member of the group selected
from L-arginine and physiologically acceptable salts of L-arginine
that enhance vasodilation through production of nitric oxide, and
(b) a cosmetically or dermatologically acceptable vehicle.
2. A composition according to claim 1 in which the polymer contains
7, 9, 11, 13 or 15 subunits.
3. A composition according to claim 1 in which the polymer contains
7, 9, 11, or 13 subunits.
4. A composition according to claim 1 in which the polymer contains
7 or 9 subunits.
5. A composition according to claim 1 selected from skin care
compositions, lip care compositions, hair care compositions, and
dental care compositions.
6. A composition according to claim 1 selected from creams,
lotions, solutions, suspensions, powders, emulsions, gels, waxy
products, powders and solids.
7. A composition according to claim 1 selected from skin-washing
and skin-cleansing preparations, soapless detergents, body lotions,
emulsions, skin oils, peeling or scrub preparations, peeling masks,
foam baths, bath milks, shower preparations, bath cubes, bath
salts, facial make-up eyeshadow, mascara, eyeliner, eye creams,
lipsticks, lip gloss, lip contour pencils, nail polish, nail
varnish, foot baths, foot powders, foot creams, foot balsams,
callous-removing preparations, sun milks, sun lotions, sun creams,
sun oils, sun blocks, pre-tanning preparations, after-sun
preparations, self-tanning creams, toothpastes, tooth powders, gum
treatment pastes, gum treatment gels, gum rinses, shampoos,
conditioners, styling creams, styling gels, hair rinses, foams,
hairsprays, hair dyes and hair colorants.
8. A composition according to claim 1 in which the subunits are
selected from L-arginine and physiologically acceptable salts of
L-arginine.
9. A composition according to claim 1 in which the subunits are
selected from L-arginine and L-arginine salts selected from the
group consisting of L-arginine sulfate, hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laureate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate and laurylsulfonate; alkali and alkaline earth metal
salts of L-arginine; and ammonium, quaternary ammonium and amine
salts of L-arginine.
10. A composition according to claim 1, further containing one or
more ingredients selected from antimicrobials, moisturizers and
hydration agents, penetration agents, preservatives, emulsifiers,
natural or synthetic oils, solvents, surfactants, detergents,
gelling agents, emollients, antioxidants, fragrances, fillers,
thickeners, waxes, odor absorbers, dyestuffs, coloring agents,
powders, viscosity-controlling agents and water, and optionally
including anesthetics, anti-itch actives, botanical extracts,
conditioning agents, darkening or lightening agents, glitter, hair
pigment additives, humectants, mica, minerals, polyphenols,
silicones or derivatives thereof, sunblocks, vitamins, and
phytomedicinals.
11. A composition according to claim 1, further containing one or
more additional skin care, lip care, dental care or hair care
active agents.
12. A composition according to claim 11 further containing one or
more ingredients selected from anti-acne actives; anti-wrinkle,
anti-skin atrophy and skin repair actives; skin barrier repair
actives; non-steroidal cosmetic soothing actives; artificial
tanning agents and accelerators; skin lightening actives; sunscreen
actives; sebum stimulators; sebum inhibitors; anti-oxidants;
protease inhibitors; skin tightening agents; anti-itch ingredients;
5-alpha reductase inhibitors; desquamating enzyme enhancers;
anti-glycation agents; and mixtures thereof.
13. A composition according to claim 1 in which the polymer further
comprises a hydrophobic, hydrophilic, or amphipathic moiety, or a
second polymer, linked or anchored to a terminal L-arginine subunit
of the polymer.
14. A composition for enhancement of keratinous tissues comprising
(a) an enhancing effective amount of a polymer having from 7 to 15
contiguous L-arginine subunits, each such subunit consisting of a
member of the group selected from L-arginine and physiologically
acceptable salts of L-arginine that enhance vasodilation through
production of nitric oxide, the polymer also containing one or more
amino acids other than L-arginine, providing that (i) such other
amino acids are not therapeutically effective and (ii) the
contiguous L-arginine subunits are situated at either the
C-terminus or the N-terminus of the polymer; and (b) a cosmetically
or dermatologically acceptable vehicle.
15. A composition according to claim 14 in which the polymer
contains 7, 9, 11, 13 or 15 contiguous L-arginine subunits.
16. A composition according to claim 14 in which the polymer
contains 7, 9, 11, or 13 contiguous L-arginine subunits.
17. A composition according to claim 14 in which the polymer
contains 7 or 9 contiguous L-arginine subunits.
18. A composition according to claim 14 selected from skin care
compositions, lip care compositions, hair care compositions, and
dental care compositions.
19. A composition according to claim 14 selected from creams,
lotions, solutions, suspensions, powders, emulsions, gels, waxy
products, powders and solids.
20. A composition according to claim 14 selected from skin-washing
and skin-cleansing preparations, soapless detergents, body lotions,
emulsions, skin oils, peeling or scrub preparations, peeling masks,
foam baths, bath milks, shower preparations, bath cubes, bath
salts, facial make-up eyeshadow, mascara, eyeliner, eye creams,
lipsticks, lip gloss, lip contour pencils, nail polish, nail
varnish, foot baths, foot powders, foot creams, foot balsams,
callous-removing preparations, sun milks, sun lotions, sun creams,
sun oils, sun blocks, pre-tanning preparations, after-sun
preparations, self-tanning creams, toothpastes, tooth powders, gum
treatment pastes, gum treatment gels, gum rinses, shampoos,
conditioners, styling creams, styling gels, hair rinses, foams,
hairsprays, hair dyes and hair colorants.
21. A composition according to claim 14 in which the L-arginine
subunits are selected from L-arginine and physiologically
acceptable salts of L-arginine.
22. A composition according to claim 14 in which the L-arginine
subunits are selected from L-arginine and L-arginine salts selected
from the group consisting of L-arginine sulfate, hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate oleate, palmitate, stearate, laureate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate and laurylsulfonate; alkali and alkaline earth metal
salts of L-arginine; and ammonium, quaternary ammonium and amine
salts of L-arginine.
23. A composition according to claim 14, further containing one or
more additional skin care, lip care, dental care or hair care
active agents.
24. A composition according to claim 23 further containing one or
more active compounds selected from anti-acne actives;
anti-wrinkle, anti-skin atrophy and skin repair actives; skin
barrier repair actives; non-steroidal cosmetic soothing actives;
artificial tanning agents and accelerators; skin lightening
actives; sunscreen actives; sebum stimulators; sebum inhibitors;
anti-oxidants; protease inhibitors; skin tightening agents;
anti-itch ingredients; 5-alpha reductase inhibitors; desquamating
enzyme enhancers; anti-glycation agents; and mixtures thereof.
25. A composition according to claim 14, further containing one or
more ingredients selected from antimicrobials, moisturizers and
hydration agents, penetration agents, preservatives, emulsifiers,
natural or synthetic oils, solvents, surfactants, detergents,
gelling agents, emollients, antioxidants, fragrances, fillers,
thickeners, waxes, odor absorbers, dyestuffs, coloring agents,
powders, viscosity-controlling agents and water, and optionally
including anesthetics, anti-itch actives, botanical extracts,
conditioning agents, darkening or lightening agents, glitter, hair
pigment additives, humectants, mica, minerals, polyphenols,
silicones or derivatives thereof, sunblocks, vitamins, and
phytomedicinals.
26. A composition according to claim 14 in which the polymer
further comprises a hydrophobic, hydrophilic, or amphipathic
moiety, or a second polymer, linked or anchored to a terminal
L-arginine subunit of the polymer.
27. A method of prophylactically or therapeutically caring for the
skin, hair, lips or gums comprising applying thereto an enhancing
effective amount of a composition according to claim 1.
28. A method according to claim 27 in which the composition is
applied topically.
29. A method according to claim 27 in which the composition is
applied to promote angiogenesis in hair follicles.
30. A method according to claim 27 in which the composition is
applied to alleviate signs of aging in skin.
31. A method according to claim 27 in which the composition is
applied to enhance the appearance of lips.
32. A method according to claim 27 in which the composition is
applied to enhance sensitivity of skin.
33. A method according to claim 27 in which the composition is
applied for stabilization or remodeling of fat.
34. A method according to claim 27 in which the composition is
applied for treatment of gum regression.
36. A method of prophylactically or therapeutically caring for the
skin, hair, lips or gums comprising applying thereto an enhancing
effective amount of a composition according to claim 14.
37. A method according to claim 36 in which the composition is
applied topically.
38. A method according to claim 36 in which the composition is
applied to promote angiogenesis in hair follicles.
39. A method according to claim 36 in which the composition is
applied to alleviate signs of aging in skin.
40. A method according to claim 36 in which the composition is
applied to enhance the appearance of lips.
41. A method according to claim 36 in which the composition is
applied to enhance sensitivity of skin.
42. A method according to claim 36 in which the composition is
applied for stabilization or remodeling of fat.
43. A method according to claim 36 in which the composition is
applied for treatment of gum regression.
Description
BACKGROUND
[0001] L-arginine is a naturally occurring amino acid, which
participates in many important biochemical reactions essential to
the normal physiology of an organism. This amino acid is found in
most proteins consumed in our daily diet and can be metabolized to
support glucose synthesis or catabolized to produce energy. In
addition to L-arginine's important biochemical roles, it has also
been found to be the immediate precursor of the endogenous
vasodilator substrate found in the arterial blood vessels termed
endothelial-derived relaxing factor (EDRF), which is chemically
identical to nitric oxide (NO). Nitric oxide is present in
macrophages and thought to mediate a number of cytotoxic
actions.
[0002] Present in all cells in the body, NO, formed from L-arginine
by nitric oxide synthase (NOS), is believed to be essential in
homeostatic processes. Normally, NO has a very short
half-life--only 3-5 seconds--due to rapid inactivation by
oxyhemoglobin in the formation of methemoglobin. Modifications in
the function of NO within the cardiovascular system have been
associated with numerous diseases that seem to stem from
endothelial cells lining blood vessels (von der Leyen et al., "Gene
therapy inhibiting neointimal lesion in vivo transfer of
endothelial cell nitric oxide synthase gene," Proc Natl Acad Sci
USA, 92(4): 1137-1141 (1995)). Endothelial cells may produce
locally acting paracrine factors that favor vasodilatation,
inhibition of cell proliferation and maintenance of blood fluidity,
which are all characteristics of a healthy vascular system. NO is
one of the factors that exhibit these effects (von der Leyen et
al., "Gene therapy inhibiting neointimal lesion in vivo transfer of
endothelial cell nitric oxide synthase gene," Proc Natl Acad Sci
USA, 92(4): 1137-1141 (1995)).
[0003] In highly vascularized tissues such as lips, gums,
genitalia, etc, vasodilatation leads to transient, reversible
increases in tissue mass and sensitivity. A method for enhancing
vasodilatation in these tissues would therefore lead to a tissue
with enlarged appearance for the duration of vasodilatation--a
limiting factor for current products. For all skin, cutaneous
vasodilatation creates a natural blush appearance and can enhance
superficial skin temperature. Additionally, appearance of certain
fine lines and wrinkles might be lessened, leading to additional
cosmetic benefits. For cosmetic purposes, enhanced lip size has
become desirable. Natural appearing changes in skin and lip color
have also become important drivers for cosmetics. For highly
innervated structures such as genitalia, these same changes will
lead to increased sensitivity to stimulation as well as increased
turgor. Additionally, structures such as gums regress with age and
with inappropriate care (hard toothbrush bristles, etc). This
regression is still thought to be irreversible. However, the
appearance might be mitigated by vasodilatation for at least a
transient cosmetic benefit.
[0004] Research has also shown that NO from NO donors or
modification of nitric oxide synthesis upregulates the expression
of VEGF (vascular endothelial growth factor) in vascular smooth
muscle cells (Jozkowicz et al., "Genetic augmentation of nitric
oxide synthase increases the vascular generation of VEGF,"
Cardiovascular Res, 51:773-783 (2001)). Vascular endothelial growth
factor is of major importance for skin vascularization. Expression
of VEGF is increased in hyperplastic epidermis of psoriasis (Detmar
et al., "Overexpression of vascular permeability factor/vascular
endothelial growth factor and its receptors in psoriasis," J Exp.
Med., 180:1141-1146 (1994)), in wound healing (Brown et al.,
"Expression of vascular permeability factor (vascular endothelial
growth factor) by epidermal keratinocytes during wound healing," J
Exp. Med., 176:1375-1379 (1992)), and in other skin diseases
characterized by enhanced angiogenesis (Brown et al., "Increased
expression of vascular permeability factor (vascular endothelial
growth factor) in bullous pemphigoid, dermatitis herpetiformis, and
erythema multiforme," J. Invest. Dermatol., 104:744-749 (1995);
Brown et al., "Overexpression of vascular permeability factor
(VPFNEGF) and its endothelial cell receptors in delayed
hypersensitivity skin reactions," J. Immunol., 154:2801-2807
(1995)). The hair follicle undergoes distinct cyclic expansion and
regression that leads to rapidly changing needs for its vascular
support. Adequate supply of blood is a prerequisite for normal cell
growth and differentiation. The hair follicle undergoes a life-long
cyclic transformation. There are three phases of the hair growth
cycle: anagen, catagen and telogen. The anagen phase is involved
with rapid proliferation of follicular keratinocytes and elongation
and thickening of the hair (Yano et al., "Control of hair growth
and follicle size by VEGF-mediated angiogenesis," The J. Clin.
Invest., 107:409-417 (2001)). After anagen is completed, the hair
enters the catagen phase. In the catagen phase, the matrix cells
gradually stop dividing and eventually keratinize. This phase is
short and usually lasts about 2-3 weeks. When full keratinization
is achieved, the hair enters the last phase of the cycle, telogen.
During the telogen (resting) phase, keratinized hair falls out, and
a new matrix is gradually formed from the stem cells in the basal
layer of the outer epithelial root sheath bulge (Jankovic et al.,
"The control of hair growth," Dermatology Online Journal, 4(1), 2).
Afterwards, a new hair starts to grow and the follicle is back in
the anagen phase.
[0005] Research findings demonstrate that pronounced angiogenesis
occurs during murine hair follicle cycling (Yano et al., "Control
of hair growth and follicle size by VEGF-mediated angiogenesis,"
The J. Clin. Invest., 107:409-417 (2001)). Overexpression of VEGF
in follicular keratinocytes resulted in accelerated hair regrowth
and in increased sized of hair follicles (Yano et al., "Control of
hair growth and follicle size by VEGF-mediated angiogenesis," The
J. Clin. Invest., 107:409-417 (2001)). This result provides first
direct evidence that promotion of angiogenesis can promote hair
growth and also hair thickness. However, VEGF-induced vascular
permeability appears dependent on both NO production and
prostaglandin production (Murohara et al., "Vascular endothelial
growth factor/vascular permeability factor enhances vascular
permeability via nitric oxide and prostacyclin," Circulation,
97:99-107 (1998)). In mice lacking the eNOS gene, impaired
angiogenesis was not improved by administration of VEGF, which
suggests that eNOS is downstream from VEGF (Murohara et al.,
"Nitric oxide synthase modulates angiogenesis in response to tissue
ischemia.," J. Clin. Invest., 111:2567-2578 (1998)). Endothelial
nitric oxide synthase is a downstream mediator for in vivo
angiogenesis (Murohara et al., "Nitric oxide synthase modulates
angiogenesis in response to tissue ischemia.," J. Clin. Invest.,
111 :2567-2578 (1998)). Promoting eNOS activity by administration
of L-arginine accelerates in vivo angiogenesis (Murohara et al.,
"Nitric oxide synthase modulates angiogenesis in response to tissue
ischemia.," J. Clin. Invest., 111:2567-2578 (1998)). Therefore, NO
may help to promote hair regrowth and increased size of hair
follicles.
[0006] Nitric oxide is a vasodilator that broadly inhibits DNA
synthesis and limits cell proliferation. However, NO diffuses
freely and cannot be stored in any topical base and so cannot be
delivered topically. An approach to this problem would be to use
L-arginine, but studies have shown that the amino acid does not
cross skin effectively and also cannot be applied topically.
SUMMARY OF THE INVENTION
[0007] It has now been found that oligomers of L-arginine may be
used to provide cosmetic and other enhancements to keratinous
tissues such as skin, hair, lips and gums through vasodilation.
[0008] In one embodiment this invention comprises a topical
composition for enhancement of keratinous tissues such as skin,
lips, hair, or gums comprising (a) an enhancing effective amount of
an oligomer having from 7 to 15 subunits, each subunit consisting
of a member of the group selected from L-arginine and
physiologically acceptable salts of L-arginine that enhance
vasodilation through production of nitric oxide, and (b) a
cosmetically or dermatologically acceptable vehicle.
[0009] In another embodiment, this invention comprises a method of
prophylactically or therapeutically caring for the skin, hair, lips
or gums comprising applying thereto an enhancing effective amount
of the above composition.
[0010] These and further embodiments are described in more detail
below.
DETAILED DESCRIPTION OF THE INVENTION
[0011] This invention relates to compositions and methods for
cosmetic and other enhancement of keratin tissues such as skin,
hair, lips and gums by applying a cosmetically or dermatologically
acceptable composition that contains an enhancing effective amount
of an oligomer of L-arginine (also referred to as
"oligoarginine").
[0012] Oligoarginine complexes have been shown to carry some agents
across skin when covalently bound (Kown et al., "L-arginine polymer
mediated inhibition of graft coronary artery disease after cardiac
transplantation," Transplantation, 71:1542-1548 (2001); Wender et
al., "The design, synthesis and evaluation of molecules that enable
or enhance cellular uptake: Peptoid molecular transporters," Proc
Natl Acad Sci USA, 97(24): 3003-13008 (2000)). For example,
cyclosporin linked to a heptamer of arginine has been shown to
penetrate the skin effectively (Rothbard et al., "Conjugation of
arginine oligomers to cyclosporin A facilitates topical delivery
and inhibition of inflammation," Nat Med, 6:1253-1257 (2000)) [see
also U.S. Pat. No. 6,306,993]. Numerous drugs are available for the
treatment of primary cutaneous disease. However, these drugs are
only effective when given systemically and are ineffective when
administered topically because of poor absorption. in any case,
what has been shown in the above-cited literature is that oligomers
of arginine have been shown to provide delivery of other
therapeutic agents. In contrast, the present invention is directed
to the use of arginine oligomers as prophylactic or
therapeutic/cosmeceutical agents in their own right, in treating
keratinocyte tissues.
[0013] By "arginine oligomers" or, as described above, a polymer
that contains arginine-type subunits, is meant a polymer that
contains from 7 to 15, preferably 7, 9, 11, 13 or 15, more
preferably 7, 9, 11 or 13, and most preferably 7 or 9 subunits,
each subunit consisting of the amino acid L-arginine or of a
physiologically acceptable salt of L-arginine that enhances keratin
tissues by enhancing vasodilation through production of nitric
oxide.
[0014] In one embodiment, the arginine oligomer consists solely of
arginine. In another embodiment, however, it may be included in a
somewhat larger polymer or peptide that contains other amino acids
(e.g., glycine), providing that (a) such other amino acids are not
therapeutically effective and (b) the arginine oligomer is situated
at either the C-terminus or the N-terminus of the polymer or
peptide. One example of such a peptide is gly.sub.3-arg.sub.7.
[0015] Suitable salts of L-arginine that may be used in these
oligomers or polymers are those that are physiologically
acceptable, i.e. salts that may be used in contact with skin, lips,
hair or gums without causing any undesirable or deleterious
effects. Examples of suitable salts include, but are not limited
to, L-arginine hydrobromide, hydrochloride, sulfate, bisulfate,
nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate,
laureate, borate, benzoate, lactate, phosphate, tosylate, citrate,
maleate, fumarate, succinate, tartrate, naphthylate mesylate,
glucoheptonate, lactiobionate and laurylsulfonate salts and the
like. The salts may include alkali or alkaline earth metal cations,
such as sodium, lithium, potassium, calcium, magnesium and the
like, as well as nontoxic ammonium, quaternary ammonium and amine
cations such as ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine,
ethylamine and the like. (See, for example, Berge S. M. et al.,
"Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977) which is
incorporated herein by reference.) Among salts, the hydrochloride
salt is preferred.
[0016] The L-arginine oligomers (both those forms that are
oligomers containing solely L-arginine and those forms in which the
L-arginine is included in a larger peptide) may also be provided in
the form of derivatives that serve as sources of the L-arginine
oligomers, including derivatives in which the oligomer is linked or
anchored to a polymer (with or without degradable linkages) or to a
hydrophobic, hydrophilic, or amphipathic compound, for instance, a
polyol.
[0017] Compositions of the present invention may be used for a
number of cosmetic or dermatological treatments or purposes. Hair
care treatments include application of topical oligoarginine
formulations to prevent hair loss or to promote hair regrowth on
the scalp, or to increase the length and/or thickness of eyelashes
and/or eyebrows. Compositions may be applied to lips for purposes
such as improving the cosmetic appearance of lip contour and/or lip
color, or for expansion of lip plumpness. Topical applications may
be made to skin to reduce the appearance of wrinkles and fine
lines, to reduce the appearance of excess tissue around the eyes
(i.e., puffiness), to provide a natural blush appearance and effect
to skin, or for other cosmetic benefits. Compositions of this
invention may also be used to provide increased sensitivity, for
example to increase genital sensation or turgor or to provide hand
or foot warming.
[0018] Compositions may also be applied for dental purposes, e.g.,
to reduce the appearance of gum regression, or to induce gum
regeneration.
[0019] The compositions of this invention are preferably in the
form of products to be applied to the lips, the eyes, the skin, or
the gums of humans. They therefore contain a cosmetically or
dermatologically acceptable vehicle or medium, i.e. a vehicle or
medium that is compatible with the tissues to which they will be
applied.
[0020] The term "cosmetically or dermatologically acceptable," as
used herein, means that the compositions or components thereof so
described are suitable for use in contact with these tissues
without undue toxicity, incompatibility, instability, allergic
response, and the like.
[0021] In addition, compositions of the invention may comprise any
ingredient conventionally used in the fields under consideration,
and particularly in cosmetics and dermatology.
[0022] The term "effective amount" as used herein means an amount
of a compound, composition or oligomeric arginine according to this
invention that is sufficient to significantly induce a positive
benefit, preferably a positive skin, lip, hair, etc., appearance,
or a sensory benefit, but that implicitly is a safe amount, i.e.
one that is low enough to avoid serious side effects.
[0023] In practice, compositions of this invention include various
types of compositions and formulations typically used for cosmetic
and other care of the skin, hair, lips and gums and include, for
instance:
[0024] skin-care preparations, e.g. skin-washing and cleansing
preparations, soapless detergents, body lotions, emulsions, or skin
oils, and preparations for cleansing and caring for blemished skin,
e.g. peeling or scrub preparations or peeling masks;
[0025] bath preparations, e.g. liquid (foam baths, milks, shower
preparations) or solid bath preparations, e.g. bath cubes and bath
salts;
[0026] cosmetic personal care preparations, e.g. facial make-up in
the form of day creams or powder creams, face powder, rouge or
cream make-up;
[0027] eye-care preparations, e.g. eyeshadow, mascara, eyeliner, or
eye creams;
[0028] lip-care preparations, e.g. lipsticks, lip gloss, or lip
contour pencils;
[0029] nail-care preparations, such as nail polish and nail
vanish;
[0030] foot-care preparations, e.g. foot baths, foot powders, foot
creams or foot balsams, special deodorants and antiperspirants or
callous-removing preparations;
[0031] light-protective preparations, such as sun milks, lotions,
creams and oils, sun blocks or tropicals, pre-tanning preparations
or after-sun preparations; skin-tanning preparations, e.g.
self-tanning creams;
[0032] dental-care and mouth-care preparations, e.g. toothpastes or
tooth powders and pastes, rinses or gels for gum treatment; and
[0033] hair-treatment or hair-care preparations, e.g., shampoos,
conditioners, styling creams, styling gels, hair rinses, foams,
hairsprays, or hair dyes and colorants.
[0034] In terms of their physical form, compositions of this
invention may include solutions, emulsions (including
microemulsions), suspensions, creams, lotions, gels, waxy products
such as lipstick, powders, and solids of various types.
[0035] Such compositions will contain, in addition to the
oligomeric arginines of this invention, other ingredients typically
used in such products, such as antimicrobials, moisturizers and
hydration agents, penetration agents, preservatives, emulsifiers,
natural or synthetic oils, solvents, surfactants, detergents,
gelling agents, emollients, antioxidants, fragrances, fillers,
thickeners, waxes, odor absorbers, dyestuffs, coloring agents,
powders, viscosity-controlling agents and water, and optionally
including anesthetics, anti-itch actives, botanical extracts,
conditioning agents, darkening or lightening agents, glitter, hair
pigment additives, humectants, mica, minerals, polyphenols,
silicones or derivatives thereof, sunblocks, vitamins, and
phytomedicinals.
[0036] In addition to the oligomeric arginines, the compositions
may contain other active ingredients used in skin, lip, hair or
dental care. For instance, they may contain anti-acne actives;
anti-wrinkle, anti-skin atrophy or skin repair actives; skin
barrier repair actives; non-steroidal cosmetic soothing actives;
artificial tanning agents and accelerators; sunscreen actives;
sebum stimulators; sebum inhibitors; anti-oxidants; protease
inhibitors; skin tightening agents; anti-itch ingredients;
desquamating enzyme enhancers; anti-glycation agents; and mixtures
of such actives.
[0037] In one embodiment or application, compositions of the
present invention are useful for regulating signs of skin aging,
particularly visible and/or tactile discontinuities in skin texture
associated with aging. "Regulating the signs of skin aging"
includes prophylactically regulating and/or therapeutically
regulating one or more of such signs (similarly, regulating a given
sign of skin aging, e.g., lines, wrinkles or pores, includes
prophylactically regulating and/or therapeutically regulating that
sign). As used herein, prophylactically regulating such signs
includes delaying, minimizing and/or preventing signs of skin
aging. As used herein, therapeutically regulating such signs
includes ameliorating, e.g., diminishing, minimizing and/or
effacing signs of skin aging.
[0038] By "signs of skin aging" is meant outward visibly and
tactilely perceptible manifestations as well as other macro or
micro effects due to skin aging. These signs include the
development of textural discontinuities such as wrinkles, including
both fine superficial wrinkles and coarse deep wrinkles, skin
lines, crevices, bumps, large pores, scaliness, flakiness and/or
other forms of skin unevenness or roughness, loss of skin
elasticity, sagging (including puffiness in the eye area and
jowls), loss of skin firmness, loss of skin tightness, loss of skin
recoil from deformation, discoloration (including undereye
circles), blotching, sallowness, hyperpigmented skin regions such
as age spots and freckles, keratoses, abnormal differentiation,
hyperkeratinization, elastosis, collagen breakdown, and other
histological changes in the stratum corneum, dermis, epidermis, the
skin vascular system (e.g., telangiectasia or spider vessels), and
underlying tissues, especially those proximate to the skin.
[0039] Such signs may be induced or caused by intrinsic factors or
by extrinsic factors, e.g., chronological aging and/or
environmental damage. It should be noted, however, that the present
invention is not limited to regulation of the above mentioned signs
of skin aging which arise due to mechanisms associated with skin
aging, but is intended to include regulation of said signs
irrespective of the mechanism of origin.
[0040] The present invention is especially useful for
therapeutically regulating visible and/or tactile discontinuities
in mammalian skin texture, including texture discontinuities
related to skin aging. This includes ameliorating, e.g.,
diminishing, minimizing and/or effacing visible and/or tactile
discontinuities in the texture of mammalian skin, to thereby
provide improved skin appearance and/or feel, e.g., a smoother,
more even appearance and/or feel. For example, the length, depth,
and/or other dimension of lines and/or wrinkles may be decreased,
the apparent diameter of pores may decrease, or the apparent height
of tissue immediately proximate to pore openings may decrease so as
to approach that of the interadnexal skin.
[0041] The present invention is also useful for prophylactically
regulating visible and/or tactile discontinuities in mammalian skin
texture, including texture discontinuities associated with skin
aging, that is, delaying, minimizing and/or preventing visible
and/or tactile discontinuities in the texture of skin, to thereby
provide improved skin appearance and/or feel, e.g., a smoother,
more even appearance and/or feel.
[0042] The compositions of the present invention may also be used
for stabilization or remodeling of hypodermal or deeper fat. Fat
stabilization, particularly in humans, is generally associated with
the appearance of aging attributed to fat atrophy as well as fat
regression in the skin. The methods and compositions described
herein can assist in preventing the formation of wrinkles and aid
in ameliorating the appearance of deep wrinkles by supporting
vascularity of the skin.
[0043] The following represent examples of compositions and uses of
such compositions in accordance with this invention. However, these
are presented solely as examples, and are not intended to limit the
scope and nature of this invention in any way.
EXAMPLES
Example 1
Topical Enhancement of Hair Growth (Eyelash, Eyebrow or Scalp)
[0044] A preparation of
(L-arg)-(L-arg)-(L-arg)-(L-arg)-(L-arg)-(L-arg)-(L-
-arg)-(L-arg)-(L-arg) or [LR9] was obtained from Sigma Genosys at
>70% purity. To achieve a therapeutic benefit on hair growth, a
10.times. stock of LR9 was prepared as 70 mg in 80 .mu.l PBS. To
0.2 ml of Cetaphil moisturizer base was added the following:
[0045] LR9: 20 .mu.l of 10.times. LR9 stock
[0046] Control: 20 .mu.l PBS
[0047] After addition of LR9/PBS to moisturizer base, samples were
mixed to homogeneity and stored at 4C overnight. C57 black six mice
at 8 weeks of age were anesthetized with 3% isoflurane by
inhalation, were shaved, and underwent depilation at mid-scapular
dorsal region of 2 cm.times.2 cm with a rosin mixture (Surgiwax,
Ardell, Commerce, Calif.) to induce the synchronized adolescent
first hair cycle. Moisturizer was applied daily at 0.2 cc per day
for either LR9 treatment or control for a fourteen day period at
n=4 per group. After 14 days application the treated skin segment
was harvested en bloc and subdivided into three equal portions: a
cranial portion, a left lateral portion and a right lateral
portion. The cranial portion and the left lateral portion were
fixed in 10% neutral buffered formalin for 12-16 hours, then rinsed
in 70% ethanol and embedded in paraffin. The right lateral portion
was snap frozen in OCT medium at the time of harvest and stored at
-35C until use.
[0048] Paraffin-embedded specimens were sectioned at 4-6 microns,
deparaffinized, and stained with a combination of Verhoeff elastica
stain and the Masson trichrome stain for morphological assessment
of follicle area and number. Frozen samples underwent random hair
pulls to determine hair shaft length. All procedures and analyses
were performed by blinded observers. High resolution digital
micrographs of each preparation were obtained using a Diagnostic
Instruments SPOT camera (Diagnostic Instruments, Sterling Heights,
Mich.) as displayed on a Nikon E600 epifluorescence microscope with
plan-apochromat lenses. Images were analyzed using Image Pro Plus
software (Media Cybernetics, Silver Spring, Md.) to determine total
cross-sectional follicle area, follicle number, or hair length.
Mean and standard error were assessed using Statview (Abacus
Concepts, Berkeley, Calif.), with comparisons made using ANOVA
repeated measures and significance determined at 95% with post-hoc
testing using Fisher PLSD or Scheffe F-test.
[0049] Results are as follows:
[0050] Hair Shaft Length (pixels [1 pixel (for length)=2.774
microns], 14 days)
1 Group: Mean: Std. Error: LR9 1612.424 93.743 control 1131.009
60.44 Comparison anova (95) LR9 vs. control ** ** = significant by
fisher PLSD and Scheffe F-test (P = 0.0001)
[0051] Follicle Area (square pixels [1 square pixel (for area)=7.69
square microns], 14 days)
[0052] (by total x-sectional area)
2 Group: Mean: Std. Error: LR9 53546.00 3204.922 control 32458.333
2477.525 Comparison anova (95) LR9 vs. control ** ** = significant
by fisher PLSD and Scheffe F-test (P = 0.0001)
[0053] Number of follicles per cross-section (14 days)
3 Group: Mean: Std. Error: LR9 406.417 15.314 control 304.5 22.626
Comparison anova (95) LR9 vs. control ** ** = significant by fisher
PLSD and Scheffe F-test (P = 0.0001)
[0054] Thus, in the present example, LR9 was shown able, without
any additional transdermal delivery platform, to statistically
significantly enhance hair growth as measured by hair shaft length,
total follicle area, and number of hair follicles.
Example 2
Topical Lip Color and Contour Enhancement
[0055] A preparation of
(L-arg)-(L-arg)-(L-arg)-(L-arg)-(L-arg)-(L-arg)-(L-
-arg)-(L-arg)-(L-arg) or [LR9] was obtained from Sigma Genosys at
>70% purity. To achieve a therapeutic benefit on hair growth, a
1.times. stock of LR9 for lip enhancement was prepared as 35 mg in
50 .mu.l pbs, which was added to 2.0 ml of Revlon Lip Gloss base
for the following groups:
[0056] LR9
[0057] Control (base only)
[0058] After addition of LR9 to lip gloss base, samples were mixed
to homogeneity and stored at room temperature overnight. After
baseline image acquisition using a Minolta Dimage 7 digital camera
set to 105 macro (1:1) with standard lighting and scaling
conditions, human subjects underwent topical application of LR9 or
control gloss. All participants were blinded with respect to
treatment or control application. Additional digital micrographs
were acquired at time 0, 1, 5, 10, 15, and 30 minutes after lip
gloss application. The gloss was then removed and participants
asked to record duration of any lip contour or color changes.
Additionally, any complications (irritation, etc) were also tracked
for each. Each subject was treated at different timepoints with
both groups (treatment or control). Image analysis of total
photographic area was performed for each group, with care taken to
normalize each to scales included at the time of photograph
acquisition. Baseline images (pre-application) were verified to
have statistically similar values between pre-LR9 gloss and
pre-base gloss applications for each participant. Mean and standard
error across timepoints 1, 5, 10, 15, and 30 minutes were
determined for each participant after LR9-gloss or base gloss
application. Values for each as well as photos acquired at matching
timepoints are presented by participant below for 3
participants.
4 Mean Area Standard (sq. in.) Error Base Gloss 6.784 0.027 LR9
7.745 0.283
[0059]
[0060] [insert photos]
5 Mean Area Standard (sq. in.) Error Base Gloss 6.562 0.163 LR9
7.411 0.128
[0061]
6 Mean Area Standard (sq. in.) Error Base Gloss 7.523 0.055 LR9
7.911 0.066
[0062] No participants noted any local irritation or other
complications after administration of base gloss or LR9 gloss.
[0063] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference.
[0064] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be readily apparent to those of ordinary
skill in the art in light of the teachings of this invention that
certain changes and modifications may be made thereto without
departing from the spirit or scope of the appended claims.
* * * * *